CN104447697A - Preparation method of dabigatran etexilate intermediate - Google Patents
Preparation method of dabigatran etexilate intermediate Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention discloses a preparation method of a dabigatran etexilate intermediate. The method comprises the major steps of (1) adding 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-ethyl acrylate and ethyl chloroacetate to a reaction solution to mix and dissolve, and then adding immobilized enzyme to react; (2) removing immobilized enzyme after the reaction is finished to obtain organic layers; (3) distilling the organic layers to remove a reaction solvent so as to obtain an oily substance, and then adding acetic acid for reflux reacting; (4) distilling to remove glacial acetic acid after the reaction is finished, adding ethyl acetate and purified water, extracting, drying all obtained organic layers by distilling to obtain beta-alanine-N-[[1-methyl-1H-benzimidazole-2-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester. The method is simple to operate, mild under reaction conditions, easy to prepare a high-purity product, and high in product yield; in addition, the enzyme can be recycled, so that the preparation method has a good industrial application prospect.
Description
Technical field
The present invention relates to chemical industry and chemical medicine, particularly a kind of preparation method of dabigatran etexilate intermediate.
Background technology
Dabigatran etcxilate (dabigatran etexilate), it is the new oral anticoagulant researched and developed by German Boehringer Ingelheim company, it is the oral anticoagulation thing direct thrombin inhibitor (DTIs) of new generation of forefront, for palsy and the systemic embolism of medicine for preventing nonvalvular atrial patient, effective, predictable, stable anticoagulant effect can be provided, there is less generation drug interaction simultaneously, without advantages such as medicine food interactions.Its chemical structure is as follows:
Boehringer Ingelheim company of Germany disclosed a kind of modification method preparing dabigatran etcxilate in 2012 at patent CN 102612517.Synthetic route is as follows:
In said synthesis route, using the key intermediate of Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester (I) as synthesis dabigatran etcxilate.Its synthesis adopts the method preparation of chemosynthesis, complex operation, and yield is generally not high, and reaction is very easily by moisture effects, causes quality product and yield problem.
Summary of the invention
The present invention in order to solve the deficiency of existing preparation method, by adopting immobilized enzyme as catalyzer, obtain a kind of simple to operate, reaction conditions is gentle, be easy to obtain high purity product, the preparation method being suitable for industrial amplification production that yield is higher.
For achieving the above object, the present invention adopts following technical scheme, and a kind of preparation method of dabigatran etexilate intermediate is:
Specifically comprise the following steps:
(1) 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate and ethyl chloroacetate are joined in reaction solvent be stirred to dissolving, then add immobilized enzyme reaction;
(2) reaction terminates rear mistake and filters immobilized enzyme, adds extraction agent and purified water, collected organic layer after extraction;
(3) boiled off by the extraction agent in organic layer, gained oily matter adds glacial acetic acid back flow reaction;
(4) reaction terminates rear removing glacial acetic acid, adds ethyl acetate and distilled water wash, gained organic layer is rotated evaporate to dryness and namely obtains Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester.
In the preparation method of dabigatran etexilate intermediate provided by the invention, described in step (1), organic solvent is selected from the one in acetone, tetrahydrofuran (THF) or methylene dichloride, preferred acetone.
Wherein, in step (1), the mol ratio of 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate and ethyl chloroacetate is 1:1 ~ 1.3.Preferably, the mol ratio of 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate and ethyl chloroacetate is 1:1.
Concrete, described immobilized enzyme is selected from the one in Novozym435, candida antarctica lipase B or Lipase NS81020, preferred Novozym435.
More specifically, the mass ratio of described Novozym435 and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.2 ~ 0.5:1.
Preferably, the mass ratio of immobilized enzyme Novozym435 and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.3:1.
Concrete, the mass ratio of described candida antarctica lipase B and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.2 ~ 0.5:1; The mass ratio of described LipaseNS81020 and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 1 ~ 1.5:1.
Temperature of reaction in step (1) is 25 ~ 60 DEG C, and reaction proceeds to till Liquid Detection raw material complete reaction, generally needs reaction 5 ~ 15 hours.Preferably, the temperature of reaction in step of the present invention (1) is 25 DEG C.
In the preparation method of dabigatran etexilate intermediate provided by the invention, the extraction agent described in step (2) is selected from the one in ethyl acetate or methylene dichloride, preferably adopts ethyl acetate.
Concrete, in step (2), the volume ratio of extraction agent and purified water is 1.4 ~ 2:1.
Can recycling by filtering the immobilized enzyme that obtains in step of the present invention (2), can production cost be reduced.
In the preparation method of dabigatran etexilate intermediate provided by the invention, by mass volume ratio (g/ml), in step (3), the add-on of glacial acetic acid is 1.5 ~ 2 times of gained oily matter in reactions steps (3), temperature of reaction is 90 ~ 110 DEG C, reaction times is 1.5 ~ 2h, and reaction is reacted completely smoothly.
Preferably, the add-on of glacial acetic acid is 2 times of the oily matter in step (3), and the reaction times is 2h.
In the preparation method of dabigatran etexilate intermediate provided by the invention, with the method removing glacial acetic acid revolving steaming in step (4), the concrete temperature of revolving steaming glacial acetic acid is 60 ~ 70 DEG C, preferably 65 ~ 70 DEG C.
Namely ethyl acetate evaporate to dryness is obtained Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester, the concrete temperature of revolving steaming is 50 ~ 60 DEG C, preferably 55 ~ 60 DEG C.
In preparation method of the present invention, in step (4), the volume ratio of ethyl acetate and water is 1.4 ~ 2:1; Preferably, the volume ratio of ethyl acetate and water is 2:1.
As preferred forms of the present invention, described method is specially:
(1) 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate 100g and ethyl chloroacetate 35.8g is got, join stirring and dissolving in 200 ~ 300ml acetone, then immobilized enzyme Novozym43530g is added in above-mentioned solution, 25 DEG C are stirred 15h, and Liquid Detection raw material reaction is complete;
(2) immobilized enzyme Novozym435 is crossed filter, boil off acetone, add ethyl acetate 400ml, purified water 200ml and wash extraction, collected organic layer;
(3) ethyl acetate in step (2) gained organic layer boiled off, gained oily matter joins in 200ml glacial acetic acid at 105 DEG C of reaction 2h;
(4) react complete, boil off glacial acetic acid, add ethyl acetate 400ml purified water 200ml and wash, ethyl acetate is boiled off to obtain Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester.
The present invention utilizes immobilized enzyme (Novozym435, candida antarctica lipase B or Lipase NS81020) as catalyzer, carry out amide condensed reaction, the cyclization that then refluxes in glacial acetic acid becomes Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester.Activity of the immobilized enzyme used in the present invention is high, selectivity is strong, be easy to get and easy mistake filters, Reusability after filtering.The activity of this enzyme and traditional catalyzer such as catalyzed reaction yield compared with CDI increases but this enzyme can Reusability, thus reduces production cost.Reaction conditions of the present invention is gentle, yield is higher, easy and simple to handle, and operation steps reduces compared with traditional technology, easy and simple to handle.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
In the present embodiment, the preparation method of dabigatran etexilate intermediate Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester comprises the following steps:
(1) intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate 100g and ethyl chloroacetate 35.8g (mol ratio is 1:1) is joined stirring and dissolving in 300ml acetone, 30g immobilized enzyme Novozym435 is added in reaction solution, 25 DEG C are stirred 15h, and Liquid Detection raw material reaction is complete;
(2) immobilized enzyme Novozym435 is crossed filter, boil off reaction solvent acetone, add ethyl acetate 400ml, purified water 200ml and wash extraction, collected organic layer;
(3) organic layer ethyl acetate boiled off, gained oily matter adds 105 DEG C of reaction 2h in 200ml glacial acetic acid;
(4) reaction is finished, 65 ~ 70 DEG C revolve steaming removing glacial acetic acid, add ethyl acetate 400ml, purified water 200ml washing, at 55 ~ 60 DEG C, boil off ethyl acetate and obtain Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester.Yield 84%, Liquid Detection purity 96%.
Embodiment 2
The difference of the present embodiment and embodiment 1 is only, the acetone in step (1) is replaced with tetrahydrofuran (THF), and the yield of products obtained therefrom is 76%, Liquid Detection purity 94%.
Embodiment 3
The difference of the present embodiment and embodiment 1 is only, the acetone in step (1) is replaced with methylene dichloride, the yield 79% of products obtained therefrom, Liquid Detection purity 93%.
Embodiment 4
The difference of the present embodiment and embodiment 1 is only, the temperature of reaction in step (1) is adjusted to 10 DEG C, and other conditions are constant, and liquid phase monitoring extent of reaction, 26h reacts completely, and quality product and product yield are all low than embodiment 1.
Embodiment 5
The difference of the present embodiment and embodiment 1 is only, the temperature of reaction in step (1) is adjusted to 60 DEG C, and other conditions are constant, and liquid phase monitoring extent of reaction, 7h reacts completely, yield 64%, Liquid Detection purity 79%.
Embodiment 6
The difference of the present embodiment and embodiment 1 is only, in step (1), the add-on of immobilized enzyme Novozym435 changes 20g into by 30g, and other conditions are constant, and liquid phase monitoring extent of reaction, 32h reacts completely, yield 69%, Liquid Detection purity 85%.
Embodiment 7
The difference of the present embodiment and embodiment 1 is only, immobilized enzyme used in step (1) re-starts feed intake for embodiment 1 being filtered gained immobilized enzyme Novozym435, other conditions are constant, liquid phase monitoring extent of reaction, 16h reacts completely, yield 82%, Liquid Detection purity 95%.This embodiment illustrates that immobilized enzyme can recycling, thus reduces costs.
Embodiment 8
Embodiment 1 immobilized enzyme Novozym435 is changed into candida antarctica lipase B to re-start and feed intake, other conditions are constant, and liquid phase monitoring extent of reaction, 17.5h reacts completely, yield 85%, Liquid Detection purity 95%.
Embodiment 9
Embodiment 8 immobilized enzyme Novozym435 is changed into Lipase NS81020 to re-start and feed intake, other conditions are constant, and liquid phase monitoring extent of reaction, 17h reacts completely, yield 83%, Liquid Detection purity 94%.
As seen from the above embodiment adopt acetone as reaction solvent time, yield and content comparatively methylene dichloride and tetrahydrofuran (THF) good, and because of the toxicity of acetone less, so in step of the present invention (1) preferred acetone as reaction solvent.
The suitable range of reaction temperature that the present invention adopts is 25 DEG C to 60 DEG C, lower than or exceed this temperature range yield and content all can reduce.
The preferred immobilized enzyme Novozym435 of immobilized enzyme, the mass ratio of immobilized enzyme and intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.2-0.5:1.
In addition, this technique is without the reaction conditions of harshness, and raw material is easy to get, simple to operate, and yield is high, is suitable for amplifying producing.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. a preparation method for dabigatran etexilate intermediate, is characterized in that, comprises the following steps:
(1) 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate and ethyl chloroacetate are joined stirring and dissolving in reaction solvent, then add immobilized enzyme reaction;
(2) reaction terminates rear mistake and filters immobilized enzyme, boils off reaction solvent, adds extraction agent and purified water extracts, collected organic layer;
(3) gained organic layer is boiled off extraction agent, obtain oily matter, add glacial acetic acid back flow reaction;
(4) reaction boils off glacial acetic acid after terminating, and adds ethyl acetate and purified water, and extraction, namely obtains Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester by gained organic layer evaporate to dryness.
2. preparation method according to claim 1, is characterized in that: in step (1), the mol ratio of 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate and ethyl chloroacetate is 1:1 ~ 1.3.
3. preparation method according to claim 1, is characterized in that: described immobilized enzyme is selected from the one in Novozym435, candida antarctica lipase B, Lipase NS81020, preferred Novozym435.
4. preparation method according to claim 3, is characterized in that: the mass ratio of described Novozym435 and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.2 ~ 0.5:1.
5. preparation method according to claim 3, is characterized in that: the mass ratio of described candida antarctica lipase B and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 0.2 ~ 0.5:1; The mass ratio of described Lipase NS81020 and 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate is 1 ~ 1.5:1.
6. preparation method according to claim 1, is characterized in that: the temperature of reaction in step (1) is 25 ~ 60 DEG C.
7. preparation method according to claim 1, is characterized in that: in step (1), described reaction solvent is selected from the one in tetrahydrofuran (THF), acetone or methylene dichloride; Preferred acetone.
8. preparation method according to claim 1, is characterized in that: the extraction agent described in step (2) is selected from the one in ethyl acetate or methylene dichloride.
9. preparation method according to claim 1, it is characterized in that: by mass volume ratio, in step (3), the add-on of glacial acetic acid is 1.5 ~ 2 times of the oily matter in step (3), and temperature of reaction is 90 ~ 110 DEG C, and the reaction times is 1.5 ~ 2h.
10. preparation method according to claim 1, is characterized in that, comprises the following steps:
(1) 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzoylamino]-ethyl propenoate 100g and ethyl chloroacetate 35.8g is got, join stirring and dissolving in 200 ~ 300ml acetone, then immobilized enzyme Novozym435 30g is added in above-mentioned solution, 25 DEG C are stirred 15h, and Liquid Detection raw material reaction is complete;
(2) immobilized enzyme Novozym435 is crossed filter, boil off acetone, add ethyl acetate 400ml, purified water 200ml and wash extraction, collected organic layer;
(3) ethyl acetate in step (2) gained organic layer boiled off, gained oily matter joins in 200ml glacial acetic acid at 105 DEG C of reaction 2h;
(4) react complete, boil off glacial acetic acid, add ethyl acetate 400ml purified water 200ml and wash, ethyl acetate is boiled off to obtain Beta-alanine-N-[[1-methyl isophthalic acid H-benzimidazolyl-2 radicals-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104987323A (en) * | 2015-07-10 | 2015-10-21 | 浙江美诺华药物化学有限公司 | Preparation method of Dabigatran etexilate |
| CN111334537A (en) * | 2020-04-01 | 2020-06-26 | 中山万汉制药有限公司 | Method for synthesizing enzyme-catalyzed dabigatran etexilate intermediate |
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| CN104987323A (en) * | 2015-07-10 | 2015-10-21 | 浙江美诺华药物化学有限公司 | Preparation method of Dabigatran etexilate |
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| CN111334537A (en) * | 2020-04-01 | 2020-06-26 | 中山万汉制药有限公司 | Method for synthesizing enzyme-catalyzed dabigatran etexilate intermediate |
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Effective date of registration: 20170919 Address after: 233010 East Road, Bengbu, Anhui, No. 6288 Co-patentee after: Hefei University of Technology Patentee after: Bangbu Fengyuan Medicine Sci-Tech Development Co., Ltd. Address before: 233010 East Road, Bengbu, Anhui, No. 6288 Patentee before: Bangbu Fengyuan Medicine Sci-Tech Development Co., Ltd. |